Suppressors of variegation 3-9 homolog 1 (SUV39H1), the enzyme responsible for establishing histone H3 lysine 9 trimethylation (H3K9me3) marks in heterochromatin, is frequently dysregulated in cancers. However, the mecha...Suppressors of variegation 3-9 homolog 1 (SUV39H1), the enzyme responsible for establishing histone H3 lysine 9 trimethylation (H3K9me3) marks in heterochromatin, is frequently dysregulated in cancers. However, the mechanisms underlying SUV39H1 dysregulation in breast cancer remain largely unclear. Here, we report that protein arginine methyltransferase 1 (PRMT1) directly interacts with SUV39H1 and dimethylates it at arginine 378 (R378). PKC signaling-mediated phosphorylation of SUV39H1 at S391 enhances this interaction, thereby promoting its methylation. Notably, PRMT1 binds to SUV39H1 with higher affinity and binding free energy than MDM2, causing a structural clash that blocks MDM2-mediated ubiquitination of SUV39H1. Moreover, methylated SUV39H1 exhibits enhanced H3K9me3 methyltransferase activity and promotes tumor cell growth. A SUV39H1-derived peptide (TAT-SUV-peptide) disrupts the interaction between PRMT1 and SUV39H1, thereby reducing SUV39H1 methylation. Administration of TAT-SUV-peptide remarkably suppresses mammary tumor growth. Taken together, our findings reveal a critical phosphorylation-methylation-ubiquitination axis in controlling SUV39H1 stability and highlight its therapeutic potential through targeting SUV39H1 methylation.
The MYC transcription factor is a key regulator of growth during development and a potent cancer driver when its expression is dysregulated. Strategies to inhibit MYC oncogenic activity would mark a significant advance,...The MYC transcription factor is a key regulator of growth during development and a potent cancer driver when its expression is dysregulated. Strategies to inhibit MYC oncogenic activity would mark a significant advance, but decades of efforts to target MYC directly have not been fruitful. Understanding how MYC drives transformation and tumor growth may provide new therapeutic avenues in a variety of cancers. By intersecting two independent genome-wide screens, we identified loss of the chromatin remodeler Chromodomain-Helicase DNA-binding 1 (CHD1) as a potential synthetic lethal target in MYC-driven breast cancer. Knockdown of CHD1 in a xenograft model of MYC-driven breast cancer suppresses tumor growth in vivo. In tissue culture models, we found that knockdown of CHD1 suppresses cell proliferation and induces cell death, specifically when MYC is overexpressed. Mechanistically, we found that CHD1 is required to maintain an open chromatin landscape and a transcriptional program associated with cancer progression in MYC overexpressing breast cells. Follow-up experiments indicate that this synthetic lethality may arise from nucleolar stress and p53 activation. These findings provide new insights on the chromatin-level regulation of MYC-driven breast cancer and uncover CHD1 as a novel synthetic vulnerability and potential therapeutic target.
Glucocorticoids are frequently administered to alleviate therapy-related side effects in cancer patients, yet their role in tumor progression remains controversial and mechanistically unresolved. Here, we demonstrate tha...Glucocorticoids are frequently administered to alleviate therapy-related side effects in cancer patients, yet their role in tumor progression remains controversial and mechanistically unresolved. Here, we demonstrate that the long-acting glucocorticoid dexamethasone (Dex) exerts antitumor effects that are mediated by neutrophils. In murine models of Lewis lung carcinoma (LLC) and B16F10 melanoma, Dex markedly suppressed tumor growth and prolonged survival of tumor-bearing mice. These effects were independent of adaptive immunity, macrophages, and tumor cell-intrinsic glucocorticoid signaling, but required functional glucocorticoid receptor (GR) signaling in neutrophils. Dex-treated neutrophils exhibited longer survival and higher cytotoxicity toward tumor cells via increased production of reactive oxygen species (ROS). Disruption of this GR-ROS axis, either through neutrophil-specific GR deletion or pharmacological inhibition of ROS, abolished the antitumor activity of Dex. Together, these findings uncover a neutrophil-mediated tumoricidal function of Dex and suggest that neutrophil GR-ROS signaling may be harnessed for cancer therapy.
Gastric cancer remains a significant global health challenge. Lymph node metastasis (LNM) has been identified to be relevant to the prognosis of gastric cancer (GC). However, its mechanisms of progression and metastasis...Gastric cancer remains a significant global health challenge. Lymph node metastasis (LNM) has been identified to be relevant to the prognosis of gastric cancer (GC). However, its mechanisms of progression and metastasis are still not fully understood. Recently, S100A10 has been verified to be aberrantly expressed in various cancers. In this study, we found that S100A10 expression was significantly upregulated in metastatic GC tissues. S100A10 remarkably accelerated tumor metastasis and growth. Mechanistically, dual-luciferase assay and chromatin immunoprecipitation revealed that c-Jun could bind to the promoter region of S100A10 and activate its transcription. Meanwhile, S100A10 competitively bound to Vimentin, preventing it from interacting with ubiquitin A-52 residue ribosomal protein fusion product 1 (UBA52), which led to a reduction in K48-linked ubiquitination of vimentin and an increase in vimentin protein levels in GC cells. Subcutaneous xenograft and lung metastasis mouse models were established to prove that targeting inhibition of S100A10 could effectively suppressed tumor metastasis and growth in vivo. In conclusion, S100A10, activated by c-Jun, remarkedly promoted metastasis and proliferation in GC via suppressing vimentin-UBA52 interaction.
Colorectal cancer (CRC) remains a major global health burden with limited therapeutic options. This study identifies phosphomannomutase 2 (PMM2) as a key oncogenic driver in CRC. PMM2 is significantly upregulated in CRC...Colorectal cancer (CRC) remains a major global health burden with limited therapeutic options. This study identifies phosphomannomutase 2 (PMM2) as a key oncogenic driver in CRC. PMM2 is significantly upregulated in CRC tissues and cell lines, correlating with advanced tumor stages, lymphatic metastasis, and poor patient survival. Functional assays reveal that PMM2 knockdown inhibits CRC cell proliferation, migration, invasion, and glycolytic activity (reducing glucose uptake, ATP/lactate production, and extracellular acidification rate). Mechanistically, PMM2 interacts with transcriptional regulator TRIM28, promoting TRIM28 nuclear translocation, recruiting transcription factor E2F4, and enhancing KIFC3 transcription by binding to its promoter. KIFC3 mediates PMM2-driven glycolysis, as KIFC3 knockdown partially reverses PMM2-induced metabolic reprogramming and tumor growth in xenograft models. Patient-derived organoid studies further confirm PMM2's role in promoting CRC progression through the PMM2-KIFC3 axis. Collectively, these findings establish PMM2 as a prognostic biomarker and potential therapeutic target in CRC, highlighting its critical role in metabolic reprogramming and tumorigenesis.
Extrachromosomal DNA (ecDNA), autonomously replicating circular DNA outside the chromosomes, exists as critical oncogene driver in approximately 20% of all tumors. Massive ecDNA amplification and its asymmetric segregati...Extrachromosomal DNA (ecDNA), autonomously replicating circular DNA outside the chromosomes, exists as critical oncogene driver in approximately 20% of all tumors. Massive ecDNA amplification and its asymmetric segregation during mitotic drive high level oncogene amplification and contribute to tumor heterogeneity. Gastric cancer exhibits a high frequency of ecDNA occurrence. KRAS, a key oncogene in multiple cancers, is frequently amplified in gastric cancer; however, its functional implications via ecDNA remain largely understudied. In this study, we performed whole-genome sequencing and single-cell RNA sequencing on a gastric cancer sample to identify genomic amplification and transcription driven by ecDNA. We identified KRAS-ecDNA in gastric cancer, which exhibited significantly elevated KRAS expression and pronounced transcriptional heterogeneity. Functionally, ecDNA_High cells showed enhanced ribosome biogenesis, upregulated DNA repair pathways, differential activation of transcription factors,and reduced MHC-II signaling, indicating potential immune evasion. Drug response predictions suggested that KRAS-ecDNA_High cells are sensitive to MAPK inhibitors and upstream receptor inhibitors, despite showing broad resistance to conventional chemotherapies. Our study uncovers the critical role of KRAS-ecDNA in gastric cancer. These findings provide a rationale for targeting ecDNA-driven oncogenic programs and offer targeted strategies to combat ecDNA-mediated oncogenic evolution.
High-grade serous ovarian cancer (HGSC) is the most aggressive subtype of ovarian epithelial cancer (OEC), with characters of late-stage diagnosis, high recurrence rate, and poor survival outcomes. Fucosyltransferase 8 (...High-grade serous ovarian cancer (HGSC) is the most aggressive subtype of ovarian epithelial cancer (OEC), with characters of late-stage diagnosis, high recurrence rate, and poor survival outcomes. Fucosyltransferase 8 (FUT8) is responsible for α1,6-core fucosylation biosynthesis, and aberrant FUT8/α1,6-core fucosylation level is involved in tumor progression. However, the roles and mechanisms of protein FUT8 and α1,6-core fucosylation in HGSC tumorigenesis and progression remain elusive. Here, our study confirms that elevated levels of FUT8/α1,6-core fucose in the tissues and serum of HGSC patients, and the elevation is associated with poor patient prognosis. By applying glycoproteomic assay, we globally screen and identify NCEH1 as the specific scaffold protein of α1,6-core fucosylation. Alpha 1,6-core fucose modification stabilizes NCEH1 by preventing its degradation through proteasomal pathway. Importantly, combined with non-targeted metabolomics analysis, α1,6-core fucosylated NCEH1 facilitates LPA secretion, driving M2-like polarization of tumor-associated macrophages in the tumor microenvironment, thus leading to oncogenesis and peritoneal metastasis of HGSC in vitro and in vivo. These findings broaden the understanding of FUT8/α1,6-core fucosylation/NCEH1 in HGSC progression and metastasis, and offer glycosylated diagnostic indicators and targets for therapeutic strategies in HGSC.
Epithelial ovarian cancer (EOC) is a leading cause of gynecological cancer mortality, driven largely by late diagnosis and chemoresistance. While autophagy is critical for EOC spheroid survival during metastasis, the rol...Epithelial ovarian cancer (EOC) is a leading cause of gynecological cancer mortality, driven largely by late diagnosis and chemoresistance. While autophagy is critical for EOC spheroid survival during metastasis, the role of ULK1, a key regulator of autophagy, in EOC progression remains unclear. To investigate this, we utilized CRISPR/Cas9 technology to delete ULK1 in EOC cell lines OVCAR8, HEYA8, ES2 and the fallopian tube epithelial cell line FT190. ULK1 loss and autophagy disruption were confirmed in EOC spheroids, with reduced Beclin-1 phosphorylation, impaired LC3 processing, and p62 accumulation. ULK1 knockout decreased EOC spheroid cell viability via increased apoptosis, and impaired matrix-bound organoid growth, offering new insights into ULK1 activity in affecting EOC tumor growth and spread. These findings were supported by in vivo xenograft models, in which ULK1 loss significantly reduced tumor burden and metastatic potential. ULK1 requirement during metastasis was supported by diminished invasive capacity of ULK1 knockout spheroid cells in mesothelial clearance assays. To investigate ULK1 mechanisms contributing to EOC tumor progression and metastasis, we conducted proteomic analyses of OVCAR8 spheroids, which revealed ULK1 loss disrupted critical pathways, including MEK-MAPK, PI3K-AKT-mTOR, and apoptosis regulation. Although ULK1 knockout failed to synergize with standard-of-care chemotherapeutics, it significantly enhanced sensitivity to MEK and mTOR inhibition. Analysis of ovarian cancer datasets demonstrates that high ULK1 mRNA correlates with a poorer 10-year overall and progression-free survival; in fact, its expression is further elevated in metastases as compared with primary tumors and normal tissue. Treatment of metastatic patient-derived organoids with the clinical ULK1 inhibitor DCC-3116, MEK inhibitor trametinib, or mTORC1/2 inhibitor AZD-8055 reduced viability in a subset of these samples, reflecting inter-patient heterogeneity and need for biomarker-guided selection. Overall, this study highlights ULK1 as a critical regulator of multiple steps of EOC disease progression, underscoring its potential as a therapeutic target in advanced ovarian cancer.
Zhou J, Luo J, Wu K
… +17 more, Yun EJ, Kapur P, Pong RC, Du Y, Wang B, Authement C, Hernandez E, Yang J, Xiao G, Cha TL, Wu HC, Wu D, Margulis V, Lotan Y, Brugarolas J, He D, Hsieh JT
Autologous tumor-infiltrating lymphocyte (TIL) therapy holds transformative potential for solid tumors, yet its efficacy in glioblastoma remains limited by T cell exhaustion and immunosuppression. In the current study, w...Autologous tumor-infiltrating lymphocyte (TIL) therapy holds transformative potential for solid tumors, yet its efficacy in glioblastoma remains limited by T cell exhaustion and immunosuppression. In the current study, we optimized an effective and reliable method for in vitro expansion of TILs from glioblastoma lesions and assessed their tumor-killing capacity both in vitro and in vivo. Single-cell RNA sequencing (scRNA-seq) of expanded TILs uncovered their heterogeneity and identified a cytotoxic tissue-resident memory (TRM) CD8 TIL subset with a unique exhaustion signature. Notably, the co-stimulatory factor GITR (encoded by TNFRSF18) is highly expressed not only on immunosuppressive regulatory T (Treg) cells but also on exhausted CD8 TILs. GITR agonism via αGITR antibody achieved dual effects: it directly enhanced CD8 TIL activation while simultaneously abrogating Treg-mediated immunosuppression. This dual-action mechanism synergized with αPD-1 therapy to amplify TIL reactivation, significantly enhancing tumor control in vivo. Mechanistically, GITR activation potentiated anti-tumor responses by promoting immunological synapse (IS) formation and function in TILs via the NF-κB/KALRN signaling axis. Our findings established GITR as a crucial regulator of CD8 TIL anti-tumor immunity, positioning GITR targeting as a novel strategy to improve TIL therapy for glioblastoma, with promising implications for clinical application.
Osteosarcoma is an aggressive malignancy characterized by rapid proliferation and a propensity for metastasis. The endoplasmic reticulum (ER) chaperone GRP78, a critical regulator of osteosarcoma progression, represents...Osteosarcoma is an aggressive malignancy characterized by rapid proliferation and a propensity for metastasis. The endoplasmic reticulum (ER) chaperone GRP78, a critical regulator of osteosarcoma progression, represents a promising therapeutic target. In this study, we identified the natural compound ginkgetin (Gink) as a novel GRP78 inhibitor. Cellular thermal shift assays, surface plasmon resonance, and mutagenesis studies revealed that Gink directly binds to GRP78, with K296 serving as a key interaction site. In vitro, Gink suppressed osteosarcoma cell proliferation, migration, and invasion while inducing apoptosis and autophagy by activating the PERK-eIF2α-ATF4 pathway. Co-immunoprecipitation assays showed that Gink competitively disrupted GRP78-PERK interaction. In orthotopic and patient-derived xenograft models, Gink treatment markedly attenuated tumor growth and metastasis. Gink also reprogrammed the tumor immune microenvironment by reducing M2 macrophage polarization and synergizing with anti-PD1 therapy to enhance CD8 T-cell activity. Accordingly, Gink could be developed as a GRP78-targeting agent that triggers ER stress and immune activation, offering a dual-pronged therapeutic strategy against osteosarcoma. Ginkgetin (Gink) directly binds to GRP78 in a competitive manner, disrupting the interaction between GRP78 and PERK. This leads to PERK activation and phosphorylation, which in turn phosphorylates eIF2α to trigger ATF4 transcription. Ultimately, this cascade induces apoptosis and autophagy, inhibiting cancer progression. Additionally, Gink suppresses M2 macrophage polarization and enhances CD8 T cell cytotoxicity, both of which contribute to the prevention of cancer development.
Colorectal mucinous adenocarcinoma (MAC), a distinct subtype of adenocarcinoma (AC) characterized by extracellular mucus production. However, the specific regulatory role of mucus production in MAC development remains un...Colorectal mucinous adenocarcinoma (MAC), a distinct subtype of adenocarcinoma (AC) characterized by extracellular mucus production. However, the specific regulatory role of mucus production in MAC development remains underexplored. In this study, scRNA-seq analyses revealed that L1TD1 expression was significantly greater in MAC than in adjacent noncancerous tissues. L1TD1 is an RNA-binding protein that has been reported to regulate mRNA stability and stemness-associated transcriptional programs in cancer cells. Further experiments confirmed that L1TD1 expression was elevated in MAC compared to normal tissues and L1TD1 promoted mucus production and accelerated tumor cell proliferation and metastasis. Mechanistically, further analysis revealed the RNA recognition motif (RRM) domain of L1TD1 binds to the 3' untranslated region (3'-UTR) of ABCC3 mRNA, thus increasing its stability. In addition, ABCC3 inhibition reversed L1TD1 overexpression-induced mucus production and MAC progression. Collectively our findings demonstrate that L1TD1 binds to the GUGU motif within ABCC3 mRNA and upregulates ABCC3 expression, which subsequently activates the MAPK signaling pathway and promotes mucin production and accelerates MAC progression. These results also provide essential evidence for investigating the mechanisms of mucus production and tumor progression in MAC.
Zhang Y, Xue Z, Zhang N
… +17 more, Zhu Y, Wu Y, Lv M, Zhang Z, Mu F, Xing W, Tang Z, Wang C, Xue Z, Zhou W, Liu X, Li X, Bjerkvig R, Huang B, Han M, Wang J, Wang D
Glioblastoma (GB) is a highly complex ecosystem characterized by numerous interactions between tumor cells and the surrounding tumor microenvironment (TME). Splicing factors play a pivotal role in processing nascent pre-...Glioblastoma (GB) is a highly complex ecosystem characterized by numerous interactions between tumor cells and the surrounding tumor microenvironment (TME). Splicing factors play a pivotal role in processing nascent pre-mRNA and are important in the progression of cancer, making them promising molecular targets. In this study, we demonstrate that the DEAD-box helicase 39 A (DDX39A), a RNA helicase with several important roles in RNA metabolism and cellular processes, is significantly upregulated in GB and is primarily expressed in tumor cells, leading to an immunosuppressive macrophage polarization. Through in vitro and in vivo studies, we demonstrate that reducing DDX39A expression in GB results in reduced tumor growth and invasion. Mechanistically, through RNA-seq and RIP-seq, we identified WISP1 as a critical downstream effector of DDX39A. DDX39A stabilizes WISP1 pre-mRNA through alternative splicing regulation, thereby activating the AKT signaling pathway. We further demonstrate that WISP1, when secreted by tumor cells, functions as a paracrine signaling molecule that promotes the development of immunosuppressive tumor-associated macrophages (TAMs). Additionally, we demonstrate that Fluphenazine hydrochloride binds to and inhibits DDX39A, thereby suppressing GB growth, invasion, and the immunosuppressive function of macrophages. DDX39A thus represents a potential candidate for glioma-targeted therapy.
Williams AE, Hoffmann EJ, Inman DR
… +12 more, Gari MK, Zhou C, Burkel BM, Haidar N, Pan Y, Halambeck M, Moore BN, Wisinski KB, McGregor SM, Kerr SC, Arendt LM, Ponik SM
Recent epidemiological studies suggest that breast density and obesity together increase breast cancer risk. Although these risk factors have been explored individually, little is known about how they combine to alter th...Recent epidemiological studies suggest that breast density and obesity together increase breast cancer risk. Although these risk factors have been explored individually, little is known about how they combine to alter the tumor immune microenvironment (TIME) and promote disease progression. To address this gap, we developed a murine model of both risk factors. Spatial analysis of the TIME revealed macrophages and T-cells predominantly localized in the stroma of both risk factor groups, indicating an immune exclusion phenotype. Mice with dual risk factors had significantly increased lung metastasis. To establish the human relevance of this model, we interrogated the TIME in biopsies from 158 patients with invasive ductal carcinoma and 10 years of follow-up data. We found that patients with both risk factors had the highest incidence of metastasis (45%). Furthermore, spatial immune profiling revealed exacerbated stromal localization of macrophages and T-cells in the dual risk factor group that progressed to metastasis. Overall, we uncovered an immune exclusion phenotype in metastatic breast cancer patients with obesity and breast density, and we present a relevant murine model that parallels human disease. The murine model will enable future investigation into therapies that intercept the mechanisms by which dual risk factors modulate the TIME.
Pituitary adenomas (PAs) are intracranial tumours with severe clinical complications and increased morbidity. Stem cell-like characteristics play a crucial role in the initiation and progression of PAs. In this study, we...Pituitary adenomas (PAs) are intracranial tumours with severe clinical complications and increased morbidity. Stem cell-like characteristics play a crucial role in the initiation and progression of PAs. In this study, we identified CDK8 as a critical regulator of stemness in PA tumorigenesis. Immunohistochemical analysis demonstrated that CDK8 expression is elevated in clinical PA samples and correlates significantly with Knosp grades, indicating its potential role in parasellar invasion. Inhibition of CDK8 significantly impaired the self-renewal capacity of patient-derived PA stem-like cells (PASCs), as evidenced by reduced tumoursphere formation. To elucidate the underlying mechanism, we found that CDK8 phosphorylates the pluripotency transcription factor SOX2, thereby disrupting its interaction with the E3 ubiquitin ligase HERC5 and preventing SOX2 degradation through the ubiquitin-proteasome pathway. Moreover, pharmacological inhibition of CDK8 markedly suppressed PA cell proliferation and viability in GH3 and MMQ cell lines, primary human PA cells, and murine xenograft models. These findings revealed a novel regulatory mechanism of PA stemness and provided a promising therapeutic target for PA.
Loss of function mutations of the Hedgehog receptor PTCH1 are oncogenic drivers in some skin and brain cancers. We recently reported mutations in exons encoding the C-terminal tail of PTCH1 in colon cancer, which result...Loss of function mutations of the Hedgehog receptor PTCH1 are oncogenic drivers in some skin and brain cancers. We recently reported mutations in exons encoding the C-terminal tail of PTCH1 in colon cancer, which result in premature truncation but do not impair canonical Hedgehog signalling. In this study, we show that colon cancer cells engineered by CRISPR/Cas9 to express endogenous truncated PTCH1 have enhanced proliferation, colony formation, anchorage-independent growth and form larger tumours in vivo than isogenic cells expressing wild-type PTCH1. Analysis of the mechanisms underlying this growth advantage revealed profound transcriptional changes and unexpectedly, upregulation of GLI1 and GLI2 by a Smoothened-independent route, which proved to be necessary for the proliferative advantage. Furthermore, we found that truncation of PTCH1 C-tail upregulated several cancer-related pathways, including EGFR and Ras signalling and led to enhanced GLI-dependent PI3K activation, which exerted a positive feedback regulation on GLI expression and activity. Accordingly, PTCH1 mutant cells were highly sensitive to PI3K and GLI inhibitors and were only partially sensitive to EGFR and MEK inhibitors. Altogether, these findings reveal that PTCH1 C-tail truncating mutations promote colon cancer tumourigenesis through a non-canonical GLI-PI3K positive loop.
Esophageal squamous cell cancer (ESCC) remains an aggressive malignant tumor with limited therapeutic options and poor prognosis. This study aims to uncover novel diagnostic markers and therapeutic targets by investigati...Esophageal squamous cell cancer (ESCC) remains an aggressive malignant tumor with limited therapeutic options and poor prognosis. This study aims to uncover novel diagnostic markers and therapeutic targets by investigating molecular drivers of ESCC pathogenesis using integrated omics and functional assays. The gene expression profiles of ESCC tissues were compared with those of normal tissues. SEC14L4 expression was evaluated through qPCR, Western blot, and immunohistochemistry (IHC). Functional roles of SEC14L4 were assessed through cell proliferation, colony formation, apoptosis, migration, and invasion assays. Co-immunoprecipitation (Co-IP) and mass spectrometry were used to discover SEC14L4-interacting proteins. Ubiquitination assays assessed the degradation of DDX3X. The MAPK pathway and ferroptosis markers were analyzed by Western blot to investigate the downstream effects of SEC14L4. In vivo tumor models were used to validate SEC14L4's oncogenic role. SEC14L4 was markedly overexpressed in ESCC tissues, correlating with advanced tumor stage and reduced overall survival. In vitro, SEC14L4 promoted ESCC cell proliferation, migration, and colony formation, while inhibiting apoptosis, while its knockdown reduced these effects. DDX3X overexpression rescued these phenotypes. Co-IP and mass spectrometry confirmed a direct interaction between SEC14L4 and DDX3X, and SEC14L4 was found to inhibit DDX3X ubiquitination via RNF39. SEC14L4 promotes ESCC progression by activating the MAPK signaling pathway and inhibiting ferroptosis. In vivo, SEC14L4 knockdown significantly inhibited tumor growth. SEC14L4 facilitates ESCC development by inhibiting the ubiquitination and degradation of DDX3X by RNF39.
Retinoic acid signaling, mediated through its receptors (RARs and RXRs), plays a fundamental role in regulating cell differentiation, proliferation, and apoptosis. While well established in hematologic malignancies, part...Retinoic acid signaling, mediated through its receptors (RARs and RXRs), plays a fundamental role in regulating cell differentiation, proliferation, and apoptosis. While well established in hematologic malignancies, particularly acute promyelocytic leukemia, its therapeutic potential in breast cancer remains underexplored. Emerging evidence has identified aberrant epigenetic regulation of retinoic acid receptors as a central mechanism of resistance to retinoic acid. This review integrates recent advances in epigenetic control, receptor biology, and translational studies to re-evaluate the therapeutic potential of retinoic acid in breast cancer. Among the many factors that influence retinoic acid signaling are reduced receptor expression and altered intracellular delivery of retinoic acid. Promoter hypermethylation and histone deacetylation silence RARβ2 and disrupt canonical retinoic acid transcriptional networks, while imbalanced intracellular routing via CRABP2 and FABP5 and subtype-specific expression of RAR isoforms further determine therapeutic outcomes. Luminal tumors with preserved RARα and CRABP2 expression display strong retinoic acid sensitivity, in contrast to HER2-enriched and triple-negative subtypes, where MYC-driven CRABP2 suppression and DNA hypermethylation confer retinoid resistance. Epigenetic therapies using DNMT or HDAC inhibitors can restore RARβ2 expression and resensitize tumors. Combination regimens such as retinoic acid with entinostat and doxorubicin achieve potent antitumor synergy in preclinical models. Retinoic acid also remodels the tumor microenvironment by modulating angiogenesis, fibroblast activation, and immune responses, although stromal RARβ signaling can paradoxically promote tumor progression. Early clinical trials lacked biomarker stratification and were limited by unfavorable pharmacokinetics, likely obscuring therapeutic benefit. Future clinical development should focus on biomarker-driven patient stratification, pharmacological optimization, and rational combination strategies that integrate retinoids with targeted or immune-based therapies. Notably, emerging methylation-based classifiers that identify retinoid-responsive triple-negative breast cancer subsets, together with the paradoxical pro-tumorigenic effects of stromal RARβ, underscore the novelty and translational significance of integrating tumor-intrinsic and microenvironmental determinants of retinoid sensitivity. Together, these approaches may help re-establish functional retinoid signaling and realize the therapeutic potential of retinoic acid in breast cancer.
Aberrant activation of the Wnt/β-catenin signaling pathway is a hallmark of colorectal cancer (CRC). Here, we identify the deubiquitinating enzyme USP17 as a critical regulator of β-catenin stability and activity in CRC....Aberrant activation of the Wnt/β-catenin signaling pathway is a hallmark of colorectal cancer (CRC). Here, we identify the deubiquitinating enzyme USP17 as a critical regulator of β-catenin stability and activity in CRC. We demonstrate that USP17 directly interacts with and deubiquitinates β-catenin, preventing its degradation and enhancing its stability. CRISPR/Cas9-mediated knockdown of USP17 in CRC-derived cell lines significantly reduced β-catenin levels and suppressed epithelial-mesenchymal transition (EMT), as evidenced by distinct morphological changes and altered expression of classical EMT markers. USP17 depletion reduced the proliferation of CRC cell lines and impaired CRC tumor growth in vivo. Conversely, USP17 overexpression in immortalized rat enterocytes elevated β-catenin levels and enhanced KRAS-induced cell proliferation. RNA sequencing and quantitative proteomic analysis of USP17-depleted CRC cells revealed significant suppression of the transcriptional coactivator function of β-catenin, impacting key oncogenic-related pathways. Our findings establish USP17 as a key regulator of β-catenin signaling and highlight its potential as a candidate therapeutic target in CRC.